PROJECT SUMMARY/ABSTRACT The proposed research builds on 13 years of experience with the Northern California Childhood Leukemia Study (NCCLS), a population-based case-control study which includes ~40% of Hispanics, a traditionally under-represented ethnic group. The proposed study will continue to use a multi- and transdisciplinary approach to comprehensively study environmental, molecular, genetic, biologic and epidemiologic factors of childhood leukemia, and to improve chemical exposure assessment. Approximately 1,000 childhood leukemia cases [830 acute lymphocytic leukemia (ALL) and 160 acute myelocytic leukemia (AML)] and ~1,230 matched controls have been enrolled with DNA for genotyping available in ~95% of subjects. The investigations proposed will examine how environmental and genetic risk factors for ALL interact, and explore the etiology of rare and understudied subtypes of childhood leukemia such as AML and other groups defined by molecular and epigenetic markers. To achieve adequate statistical power, we propose to enroll an additional ~660 childhood leukemia cases (~530 ALL; 85 AML) and ~660 matched controls using an established comprehensive, rapid reporting network of pediatric oncologists in the 38 California study counties. The resulting total sample size of ~1,660 leukemia cases (1,360 ALL, 245 AML) and 1,890 matched controls will allow us to explore hypotheses related to pre- and post-natal residential exposures to pesticides, persistent organic pollutants, and sources of benzene exposure and increased risks of ALL and AML, and how these risks may vary by leukemia subtype and be modified by variants in metabolizing genes. We will also examine the influence of immune function on the risk of childhood ALL overall, B-cell ALL and common-ALL (c-ALL) subtypes, and how these associations are modified by genes involved in the regulation of immune function. We will conduct large scale genotyping of ~10,000 gene variants, and employ a number of recently developed approaches for analysis of complex multidimensional genetic and epidemiologic data.